© 2014 Elsevier Inc.
All rights reserved.
This chapter presents the rationale that may explain why the incidence
of attention deficit hyperactivity disorder (ADHD), autism, depression and
modern diseases is relentlessly increasing, despite the billions of dollars
invested in research and medications each year. This rationale leads to the
need to investigate and treat the underlying genetic predispositions and
the nutritional causes, rather than indiscriminately medicating our young
at a time of their life when their vulnerable brains are still developing.
Throughout this chapter reference is made to genes, enzymes, nutrients
and lifestyle factors that affect mental health, including ADHD, autism,
depression, anxiety and schizophrenia. It is common sense and good sci-
ence to address these potential causal factors, in addition to addressing the
dysfunctional neurophysiology with neurotherapy.
NUTRIGENOMICS, EPIGENETICS, NUTRIENTS AND
Through the processes of meiosis and mitosis a single fertilized
egg differentiates into an embryo, and eventually into a unique baby on
account of the genetic instructions in the DNA interacting with nutrients
to form proteins and enzymes that catalyze biochemical reactions. These
nutrigenomic interactions are responsible for the composition of our body
tissues and carry out a multitude of functions in the circulatory, respiratory
digestive, cardiovascular, endocrine, central and peripheral nervous systems.
Some of these proteins and enzymes enable brain functions that make us
uniquely human, such as the ability to talk, think abstract thoughts, plan
ahead and organize our environment into complex systems to serve our
needs and promote our survival.
Nutrigenomics is the study of the interaction between genes and
nutrition. Research in this field has taught us that the nutrients in food
have complex interactions with our DNA, affecting our health outcomes
Nutrition for ADHD and Autism
and our disease risks. Everything we consume has some degree of impact
on our DNA and has a consequence at a molecular level. Through the
process of natural selection, our evolutionary ancestors adapted genetically
to daily low-grade exercise, an organic diet and a clean environment. By
the end of the Palaeolithic period, modern man had emerged as the result
of an optimum balance between genes, environment, nutrition and the
hunter–gatherer lifestyle. Today, we carry these genes and are genetically
adapted to a Palaeolithic hunter–gatherer diet and lifestyle.1,2
Epigenetics is the study of changes in inherited gene expression or
cellular phenotype caused by mechanisms other than changes in DNA
nucleotide sequence. Epigenetics research has shown that our DNA is
controlled by signals from outside the cell, and that environmental fac-
tors shape the development and function of cells. Recent scientific studies
have revealed that we can influence our health outcomes through changes
in lifestyle factors, nutrient uptake and the elimination of environmental
and other toxins; even our thoughts and feelings can affect the expression
of our genes.3 Gene expression is altered by dietary transcription factors,
such as low zinc status, or by exposure to toxic environmental substances,
such as mercury or organophosphate pesticides. Studies have shown that
gene expression patterns differ geographically between and within pop-
ulations, suggesting that environmental factors are responsible. Such
changes in gene expression can adversely affect neuronal plasticity, result-
ing in neurodevelopmental disorders such as ADHD, autism and mental
Essential nutrients help maintain normal neuronal plasticity.
Nutritional deficiencies, including deficiencies in the long-chain poly-
unsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA), the amino acid methionine, zinc and selenium, have been
shown to affect neuronal plasticity and function and produce behavioral
deficits in children, including those with ADHD.5
In 1998, Dean Ornish and colleagues demonstrated that improved
nutrition, moderate exercise, stress management techniques and increased
social support were associated with the expression of over 500 epigen-
etic genes being changed in only 3 months. These include upregulating
or turning on disease-preventing genes and downregulating or turning
off genes that promote heart disease, cancer, inflammation and oxidative
stress.6 Genetic screening for selected epigenetic gene polymorphisms that
affect health outcomes is commercially available, suggesting that the future
of healthcare may well be determined by personalized nutrigenomics and
Nutrition for ADHD and Autism 359
medicine. Some of these genes, when missing or mutated, can result in
the complete absence of key enzymes responsible for liver detoxing, or in
mild to dramatic reduction in the capacity of enzymes to carry out their
functions. Hence, a one-size-fits-all diet and generic lifestyle recommen-
dations no longer make sense in light of this emerging knowledge from
Our highly processed modern diet, with its manmade trans-fatty acids,
chemical additives, preservatives, colorings, added hormones and antibi-
otics, is affecting the delicate balance of nutrigenomic interactions and is
affecting our genome. Genetic weaknesses, which previously did not seem
to affect us, now interact with dietary nutritional deficiencies and envi-
ronmental toxins to promote the modern diseases. It is not surprising that
the rates of incidence of modern diseases, such as cancer, diabetes, heart
disease, ADHD, autism, depression, anxiety, irritable bowel syndrome and
inflammatory bowel disease, to name but a few, continue to rise despite
the billions of dollars spent each year on research and pharmaceutical
treatment, which for the most part are toxic to our genome and often
carry unacceptable side effects.
A large part of my clinical practice consists of examining these genetic
polymorphisms and recommending dietary and lifestyle changes and
nutrient supplementation to modulate the expression of these genes,
reduce toxicity and oxidative stress, modulate risk factors and promote
optimum health. Throughout this chapter I shall be outlining the rationale
for the need to test for genetic polymorphisms and nutrient levels, and for
supplementing key nutrients to optimize the physical and mental health of
patients, including children with ADHD and autism.
OMEGA-3 (n-3) AND OMEGA-6 (n-6) ESSENTIAL
FATTY ACID (EFA) BALANCE
The body cannot manufacture EFAs; therefore they must be part of
our diet. A number of studies have estimated that our modern diet pro-
vides around 20–40 times more n-6 and five to ten times less n-3 than
the Palaeolithic hunter–gatherer diet.1 Most of the n-6 in our diet comes
from vegetable sources of linoleic acid (LA) such as nuts and vegetables;
n-3 also comes from vegetable sources of alpha-linolenic acid (ALA), such
as flaxseed oil and nuts such as walnuts. However, it is the consumption
of polyunsaturated cooking oils and margarines in our modern diet that
has caused the imbalance. These fatty acids are converted to longer-chain
EFAs by elongase and desaturase enzymes (Figure 14.1), and all play a cru-
cial role in the body’s composition and functions; human beings require
the long-chain polyunsaturated fatty acids from fish for brain development
Polymorphisms in the desaturase encoding genes FADS1 and FADS2
have been associated with several n-6 and n-3 fatty acids. The relation-
ship between FADS gene cluster polymorphisms and red blood cell
(RBC) fatty acid levels in over 4000 pregnant women participating in the
Avon Longitudinal Study of Parents and Children was analyzed. The study
found that FADS polymorphisms influence maternal RBC n-3 DHA lev-
els, which affected the baby’s DHA supply during pregnancy.7 Given the
fundamental role of DHA in fetal neuronal development,8 this finding
is of particular concern. Animal studies have shown that an imbalance of
high n-6:n-3 ratio early in life leads to irreversible changes in hypotha-
lamic phospholipid composition, consistent with a dysfunction or down-
regulation of the conversion of ALA to DHA by the delta-6 desaturase
enzyme (Figure 14.1). These two findings7,9 suggest that FADS polymor-
phisms may lead to irreversible structural changes in brain cells, affecting
their function; and that for those people with FADS polymorphisms, a
higher lifetime consumption of fish and fish oils may be necessary to pre-
vent deficiencies that affect brain function.
Arachidonic acid (AA), an n-6 fatty acid, is essential for cell membrane
stability and also starts a cascade of inflammatory processes (thromboxins,
leukotrienes and prostaglandins) for the defense of cells against antigens.
EPA, an n-3 fatty acid, produces anti-inflammatory processes, protecting
cells against free radical damage and from inflammatory cytokines.10 The
ratio of AA to EPA is ideally around 1.5–3.0, and this is achieved when a
person limits his or her meat intake (a good source of AA) and consumes
deep-sea cold-water fish four or five times a week, or has an adequate
intake of fish oils as supplements. Too much AA leads to a propensity for
excessive inflammation; too little adversely affects cell membrane stability
and necessary inflammatory responses.10
Trans-fatty acids are manmade (usually resulting from heating polyun-
saturated oils) and can displace EPA and DHA from cell membranes. This
has two detrimental effects: first, the cell membrane becomes more perme-
able, allowing antigens to penetrate the cell and cause damage to intracel-
lular mechanisms; second, as the RBC AA:EPA ratio rises, the propensity for
inflammation increases. In addition, the decrease in DHA levels has a detri-
mental effect on neurodevelopment and mental health, as discussed next.
Nutrition for ADHD and Autism 361
docosahexaenoic acid (DHA)
docosapentaenoic acid (DPA)
eicosapentaenoic acid (EPA)
Arachidonic acid (AA)
-linoleic acid (GLA)
Figure 14.1 Conversion of dietary fatty acids to long-chain polyunsaturated fatty acids and eicosanoids.
The Role of DHA
DHA makes up around 25% of the dry volume of brain cells in all healthy
mammals and concentrates in neuronal synapses,11 where, in conjunction
with proteins, it modulates the synthesis, transport and release of mono-
amine neurotransmitters.12 The results of a retrospective study examin-
ing the RBC EFAs in ADHD, autism and typically developing children
are shown in Tables 14.1 and 14.2.13 The Australian Twin Behavioural
Rating Scales (revised) is a DSM-IV behavioral screening questionnaire
for ADHD, and the Test of Variables of Attention (TOVA) is a computer-
administered continuous performance task.
Note the dramatically low percentage of RBC DHA in children with
autism compared to those with ADHD and typically developing controls.
The optimum RBC DHA level is >6%, and is achievable with a diet high
in fatty cold-water fish or fish oil supplementation. In addition, children
with autism spectrum disorder (ASD) had very low RBC AA, suggesting
impaired cell membrane integrity, and therefore vulnerability to damage
from toxins and antigens.13
These results indicate that children with ASD had by far the worst
EFA profile, and those with ADHD were lagging behind their typically
developing peers. Given that DHA modulates the synthesis, transport and
release of neurotransmitters in synapses, this is not surprising. However,
many of the children with autism and ADHD had RBC DHA as low as
0.1%, while others had ratios around 4.0%. These large fluctuations suggest
that whereas DHA deficiency may constitute a major part of the etiol-
ogy of neurodevelopmental disorders, other factors are also at play. During
treatment, optimum levels (>6.0%) are achieved by aggressive supplemen-
tation with high-quality fish oil concentrate. Maintenance after 12 months
can be achieved by consuming oily fish four or more times a week.
However, our experience has shown that this is applicable only for some
children. Others seem to need to take fish oil supplements and nutrient
cofactors permanently. This is probably a result of the irreversible down-
regulation of desaturase stages, as previously discussed.9 A comprehensive
review of all the nutrients and enzyme cofactors involved in brain func-
tion is beyond the scope of this chapter. Therefore, only an overview of
those that have been shown to be involved in the attentional system and
in mood regulation is provided next.
Table 14.1 Means and Standard Deviations of Age, TOVA, ATBRS, CARS, EPA, DHA and AA Between Typically Developing, ADHD and ASD
Age TOVA ATBRS CARS % EPA % DHA % AA
TD (n = 81) 8.31 (2.53) 3.88 (1.69) 14.14 (7.49) ** 1.82 (0.96) 4.70 (1.02) 10.46 (2.08)
ADHD (n = 401) 9.10 (3.58) −3.78 (3.28) 42.43 (14.43) 0.89 (0.56) 2.28 (0.89) 9.73 (2.71)
ASD (n = 85) 5.32 (2.12) 40.71 (8.04) 0.56 (0.52) 0.85 (1.02) 6.24 (3.28)
EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; AA, arachidonic acid; ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; TD,
typically developing; TOVA, Test of Variables of Attention; ATBRS, Australian Twin Behaviour Rating Scales; CARS, Childhood Autism Rating Scale.
**Parentheses denote SD.
There are five established biogenic amine neurotransmitters: the three cat-
echolamines – dopamine, norepinephrine (noradrenaline) and epinephrine
(adrenaline) – as well as serotonin and histamine. The main monoamine
neurotransmitters, serotonin, dopamine and norepinephrine, are consid-
ered brainstem neuromodulators, because their neurons have cell bodies in
the brain stem and have projections to the limbic system and to the neo-
cortex. Neuromodulation refers to the process of dynamic modulation of
neuronal activity, at rest and during information processing. It includes (a)
the manufacture of the neurotransmitters in brain synaptic vesicles from
dietary amino acid precursors; (b) their transport in vesicles through the
synaptic cleft; (c) their release into the synaptic gap; (d) their migration to
receptor sites on the receiving neurons; (e) their effect on the receiving
neurons; and finally (f) the reuptake of any residual neurotransmitter back
into the transmitting neurons for recycling (Figure 14.2).
When a neurotransmitter is released into the synapse, it migrates
to receptors located on dendrites, cell bodies and presynaptic termi-
nals of second (receiving) neurons. Almost all monoamine receptors are
G protein-coupled receptors that activate intracellular second-messenger
molecules, such as inositol triphosphate. These molecules relay signals
from surface receptors to target molecules inside the cell, amplifying the
strength of the signal, and have an effect on the postsynaptic membranes
on the receiving neuron.
Embedded among the monoamine neurotransmitter receptors are also
G protein-coupled receptors for trace amines.14 These amines are usually
formed by the breakdown of proteins in foods. Some of the most com-
mon are tyramine (from cheese), histamine (from wine) and phenylethyl-
amine (found in chocolate). However, when the bowel environment has
an acidic pH, some gut organisms, particularly lactic acid bacteria such as
Table 14.2 Independent Sample t-test Scores of EPA, DHA and AA in ADHD and
ASD Groups Compared to a Typically Developing Sample
EPA DHA AA
TD × ADHD t(480) = −11.91* t(480) = −21.84* t(480) = −2.30*
TD × ASD t(164) = −10.64* t(164) = −30.28* t(164) = −30.28*
EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; AA, arachidonic acid.
*p < 0.05.
Nutrition for ADHD and Autism 365
Bifidobacteria, overgrow and cleave proteins to produce large amount of
amines, resulting in a much higher ratio of amines to amino acids than
under neutral pH conditions.15,16 In addition, the acidic gut conditions
inhibit the growth of Escherichia coli, which is a major producer of the
monoamine neurotransmitter precursors tryptophan, phenylalanine and
tyrosine.16 This reduces the amino acids available for neurotransmitter syn-
thesis, whereas the amines key into amine receptors and scramble neu-
rotransmission. Patients report a combination of symptoms, such as brain
fog, poor concentration, muscle aches and pain, headaches, migraines
and depression. It has been proposed that these biogenic amines may be
involved in treatment-resistant depression.17 In children the symptoms
are feelings of unease, irritability, low frustration threshold, anger out-
bursts and poor concentration. Interestingly, a diet high in refined carbo-
hydrates from cereal grains and dairy products is highly acid producing
in the bowel and promotes the growth of lactic acid bacteria promoting
amine production. These symptoms can easily be mistaken for those of
ADHD. In our experience, symptoms improve or resolve with an alkaline-
producing diet and nutrient supplementation.
Serotonin or 5-hydroxytryptamine (5HT)
Serotonin is both an excitatory and an inhibitory neurotransmitter. It is
found in enteric neurons where it modulates peristalsis, and in the brain
has receptors for
neurotransmitters Dendrite of
produce AT P
Figure 14.2 Synapse and neurotransmitters.
where it modulates calmness and good feelings. Around 2% of the amino
acid tryptophan in circulation is converted to 5-hydroxytryptophan
(5HTP) by tryptophan hydroxylase, an enzyme that uses 5-MTHF (the
active form of folate), iron, calcium and vitamin B3 as cofactors. 5-HTP
is further converted to serotonin by the enzyme dopa decarboxylase,
which uses magnesium, zinc, piridoxine-5-phosphate (P5P), the active
form of vitamin B6 and vitamin C as cofactors. In the pineal gland and
the retina, the enzyme N-acetyltransferase converts serotonin to N-acetyl
serotonin, which in turn is converted to melatonin and released into the
bloodstream and cerebrospinal fluid by the enzyme 5-hydroxyindole-O-
transferase, a process requiring the active form of vitamin B6 (P5P) as
cofactor. Melatonin promotes sleep, and its production is inhibited by day-
light; even room lighting and television watching can inhibit melatonin
production (Figure 14.3).
Suboptimal neuromodulation of brain serotonin has been linked to a
variety of adverse behaviors and mental health issues, such as aggression,
irritability, low frustration threshold, anger outbursts, depression, suicidal-
ity, obsessive–compulsive disorder, alcoholism, anxiety and affective dis-
orders. Although these associations are known, the mechanism of action
Zn, B1, P5P
Vit C, 5-MTHF, B3
B2, B3, Fe, 5-MTHF,
Vit C, Fe, SAMe
Zn, Mg, P5P, Vit C
Cu, Vit C
Zn, B1, P5P
Zn, Mg, P5P, Vit C
5-MTHF, Ca, B3
Fe, P5P, Vit C
Intestinal organisms (mainly E-Coli)
break down and denature proteins to
make amino acids and amines
Figure 14.3 Neurotransmitter amino acid precursors and major nutrient enzyme
Nutrition for ADHD and Autism 367
responsible remains largely unknown. In brain synapses the principal source
of release of serotonin is from serotonin neurons, which have cell bodies
originating in the raphe nuclei, in the brain stem. Their axons form a neu-
rotransmitter system that enervates almost every part of the central nervous
The serotonin transporter (SERT) protein transports residual sero-
tonin back into the synapse for recycling and ends the action of serotonin.
This protein is the target of many antidepressant medications, particularly
selective serotonin reuptake inhibitors, which block the action of SERT.
Polymorphisms in the promoter arm of the SERT gene can affect sero-
tonin neurotransmission, causing irritability and aggressiveness as well as
an increased susceptibility to depression.18 Nutritionally, people with this
mutation require more aggressive supplementation with 5HTP, vitamin
B6 (P5P) and vitamin C.
Effect of Diet on Serotonin and Health Outcomes
The large neutral amino acids (LNAA) such as tyrosine, valine, isoleucine,
leucine, phenylalanine and lysine compete with tryptophan for trans-
port through the blood–brain barrier. Hence, foods with a high ratio of
tryptophan to LNAA may improve 5HT production in the brain. Meals
typical of those consumed in the United States and Australia have been
shown to cause substantial variations in the plasma tryptophan:LNAA and
tyrosine:LNAA ratios, depending on the ratio of protein to carbohydrates.
The differences between the ratios generated by a high-carbohydrate low-
protein and high-protein breakfast can be >50% for tryptophan:LNAA
and 30% for tyrosine:LNAA.19 Hence, a western diet high in refined
carbohydrates, wheat and cereals, and low in proteins can cause a rise in
tryptophan, thereby increasing serotonin. Concurrently, such a diet also
causes a rise in insulin, which is required to control blood sugar lev-
els.20 However, these dietary increases in serotonin and insulin are not in
keeping with the homeostasis that existed during our evolutionary his-
tory, when meat proteins, fish, nuts, fruit and vegetables were our primary
source of food.1,2
Chronically elevated insulin levels can cause hypoglycemia, insulin
resistance, metabolic syndrome, polycystic ovarian syndrome, obesity and
type 2 diabetes. Over time, insulin resistance can cause serotonin lev-
els to drop, thereby predisposing to depression.21 Exercise is known to
activate hundreds of genes and builds up muscles through a process that
uses many amino acids, with the exception of tryptophan. Consequently,
people who exercise and build more muscle have more available trypto-
phan and higher serotonin levels, thereby downregulating depression.22
E. coli, which accounts for 80–90% of the aerobic bacteria in the
healthy large bowel, produces chorismate, which is a precursor to folic
acid, coenzyme Q10, tryptophan, phenylalanine and tyrosine. Low bowel
E. coli can result in lower tryptophan levels, and therefore lower serotonin
production. This is associated with slow bowel transit time, constipation,
irritability and depressed mood. In the past 12 years we have assessed
the extended fecal microbiology of over 300 children through Bioscreen
Medical at Melbourne University and examined their bacteria distribu-
tion. Those children with low E. coli consistently display symptoms that
include irritability, low frustration threshold, anger outbursts, poor sleep,
moodiness and tantrums, and their Z-score quantitative electroencephalo-
graph (qEEG) consistently shows low delta power. This is not surprising,
because serotonin modulates delta frequencies. However, these children
tick the boxes for ADHD and are often diagnosed as such, with a poor
response to psychostimulants. Note that poor sleep quality is often caused
by low serotonin, which is converted to melatonin to promote sleep.
Given that E. coli grows best in a neutral pH gut environment, it can
be promoted with an alkalinizing diet, low in grains and dairy and rich in
vegetables, legumes and pulses, and moderate meat intake. The diet should
produce a first morning urine pH of 6.8–7.0. In addition, when delta power
levels are low, 5HTP magnesium, zinc, vitamin B6 as P5P, and vitamin C can
also be prescribed to promote serotonin and melatonin production.
The Role of Dopamine and Norepinephrine in the
In order to understand ADHD and the effect of neurotherapy on the
brain, an understanding of the attentional system is required. Tucker and
Williamson reviewed the evidence for the underpinnings of the human
attentional system, based on the biological mechanism of attention
derived from animal dissections and studies carried out by Pribram and
McGuinness.23 They concluded that there was a self-regulating asymmet-
rical neural control network linking a frontal, primarily left, dopaminer-
gic system to a posterior, primarily right, noradrenergic system. The two
linked systems were described as a “frontal tonic activation system” and a
“posterior phasic arousal system.”24
The “tonic activation system,” centering on the forebrain basal gan-
glia, was described as providing a state of tonic motor readiness for action.
Nutrition for ADHD and Autism 369
This implied a state of alertness or vigilance, which Tucker and Williamson
argued was mediated by two related dopaminergic systems: first, the pri-
mary nigrostriatal dopamine pathways, originating in the substantia nigra
in the brain stem, enervating the caudate nucleus and putamen and han-
dling sensorimotor integration. Increased dopamine modulation restricts
the range of behaviors by increasing informational redundancy. In this
context, redundancy refers to the processing of information of inter-
est in related pathways, while simultaneously restricting the processing of
other information. Thus increased redundancy not only increases reliabil-
ity but also restricts alternative information from being processed. Second,
a related dopamine pathway, the mesocortical or mesolimbic system, with
cell bodies in the ventral tegmental bundle and connections to the nucleus
accumbens, central amygdaloid nucleus and the lateral septal nuclei, sup-
ports controlled motivated interactions with the environment. They argued
that this largely dopamine-mediated neural control system does not lin-
early increase activation but qualitatively facilitates vigilance, tight control
of motor output and purposeful behaviors.
The “phasic arousal system” was described by Tucker and Williamson
as a parietal noradrenergic system providing transient responses to changes
in sensory information or novelty in sensory channels. They suggested that
reiterative loops, which constantly compare new sensory channel patterns
to previous ones, enable the detection of novelty. The primary noradren-
ergic pathway, from the dorsal tegmental bundle, originates in the pon-
tine locus ceruleus and projects rostrally to the median forebrain bundle
and the limbic system, including the amygdala, hippocampus, thalamus and
neocortex. They proposed that norepinephrine does not linearly increase
arousal, but “qualitatively” facilitates response to perceptual input from
environmental novelty. Noradrenergic activity declines with repetitive
input (habituation), inhibits neuronal discharge and reduces the sponta-
neous background activity of neurons. Thus norepinephrine may increase
signal-to-noise ratio and augment the cell’s evoked responses to stimuli,
thereby increasing sensitivity to change.24
According to Tucker and Williamson,24 the dopaminergic system appears
to maintain the tonic level of neural activity by increasing the redundancy
of the information (decreasing alternatives) in brain channels. This was
demonstrated elegantly in the behavior of DAT-KO mice (mice with over-
stimulated dopamine pathways whose dopamine transporter was geneti-
cally knocked out).25 In novel environments, the behaviors of DAT-KO
mice became dominated by progressively fewer acts (repetitively exploring
the same arm of the maze) with increasing frequency. Hence, tonic activa-
tion produces a redundancy bias, which restricts change and tightly controls
or restricts motor output or behaviors. The qualitative regulatory effect of
activation is thus opposite to that of arousal, which reduces redundancy. Yet
for motor functions a redundancy bias applies a negative control, not unlike
the negative feedback on perceptual responsiveness provided by arousal.
Behavioral output therefore requires constant change in motor channels.24
Duff26 supported this proposed explanation of the attentional sys-
tem by demonstrating its elements in a study that examined changes in
the electrical activity of boys with ADHD following neurotherapy. The
study used steady state visually evoked potential (SSVEP) probe topogra-
phy before and after neurotherapy while the boys with ADHD performed
the CPT-AX computer-administered task. The cognitive attention task
requires subjects to press a response button on the appearance of the letter
X, only if the previous letter was an A. Figure 14.4 illustrates the changes
in activation, from pre- to postneurotherapy. A reduction in normalized
amplitude can be interpreted as increased neuronal activation, while an
increase in amplitude can be interpreted as a reduction in activation.
Note the dynamic changes in activation following neurotherapy. It has
been suggested that children with ADHD may have difficulties allocat-
ing attentional resources27 and may inefficiently tie up prefrontal circuitry,
which is needed for behavior control, instead of using presupplementary
motor areas.28 This suggestion is supported by findings from a study of
suppression of BOLD response in functional magnetic resonance imaging
while performing a reaction-time task, which found that increased visual
response time in children with ADHD was associated with an inability to
deactivate the ventromedial prefrontal cortex under increased reaction-time
task demands.29 Increased visual response time in ADHD has also been
interpreted as suggestive of reduced perceptual sensitivity and response
consistency, and was related to most ADHD symptoms.30 The suggestions
of inefficient allocation of attentional resources in ADHD, tying up pre-
frontal circuits instead of using presupplementary motor areas, leading to
reduced perceptual sensitivity and response consistency, are consistent with
Silberstein’s31 suggestion that cognitive proficiency is associated with effi-
cient functional connectivity, i.e., the rapid recruitment and release of coher-
ence between relevant brain areas contingent with task demands.
Whereas neurotherapy appears to help redress the inefficient alloca-
tion of dopamine and norepinephrine resources in the brains of children
with ADHD, the nutritional precursors needed to synthesize these
Nutrition for ADHD and Autism 371
neurotransmitters in synapses and to facilitate their transport and release in
the brain need to be optimal to facilitate neuromodulation. The following
sections explain the role of gene polymorphisms, enzymes, nutrient cofac-
tors and amino acids in this process.
ZINC AS AN ESSENTIAL NUTRIENT FOR HEALTH
Zinc compounds are found in soil and water, and in many foods.
However, the soil in many countries is generally much lower in zinc than
in countries that have a soil rich in volcanic minerals – so much so that
one-third of the world’s population has an inadequate intake of dietary
Time points in seconds
Amplitude in CPT-AX tasks referenced to preneurotherapy baseline
Figure 14.4 Steady-state visually evoked potential (SSVEP) amplitude during the tar-
get sequence in the CPT-AX task as a function of time in subjects with ADHD pre- and
postneurotherapy. The dashed horizontal line represents the mean normalized ampli-
tude for the baseline task, which was set to zero for both conditions. CPT-AX related
amplitude changes are therefore expressed as differences from the baseline. The verti-
cal lines represent the time points at which: the letter A is presented (A), the letter A
disappears and the blanking interval commences (□) and the letter X appears (X).
zinc.32 Zinc deficiency is one of the most prevalent nutritional deficiencies
in the United States. Suboptimal zinc status has been noted in children of
lower socioeconomic groups, low-birthweight infants, pregnant teenagers
and some of the elderly.33,34 In Australia, the Bureau of Statistics nutritional
surveys have found that most of the population do not have the recom-
mended daily intake of zinc. If too much zinc is consumed for the body’s
needs, less is absorbed and more is excreted in urine and feces; hence, zinc
toxicity is rare. Individual requirements for dietary zinc are determined by
the biological need to replace losses and maintain function, and the bio-
availability of zinc from the foods consumed. The amount of dietary zinc
required to replace tissue losses in individuals fully adapted to a diet low in
zinc is considered the minimal zinc requirement and is often referred to as
the recommended daily intake.33,34 Blood serum zinc levels reflect recent
dietary intake, are very variable and hence are poor indicators of tissue lev-
els. RBC zinc is a better indicator of zinc status than serum zinc, because
erythrocytes have a life of 3 months and RBC levels reflect the average
level over that period. In one study, 31% of patients were found to have low
RBC zinc levels, whereas only 10% had low plasma zinc.35
Zinc is an essential nutrient, involved in hundreds of biochemical
pathways in the body, including many involved in neurotransmitter syn-
thesis and synaptic function. Features of zinc deficiency are generally non-
specific, affecting the optimal function of a number of systems. In children
deficiency may lead to poor appetite, a decreased sense of taste and smell,
slow wound healing, skin lesions and decreased immune function. There is
considerable evidence that maternal zinc deficiency has detrimental, pos-
sibly long-lasting, effects on fetal growth, neurodevelopment and immune
system maturity. In the early 1970s a number of controlled studies of zinc
supplementation in infants and toddlers in Colorado demonstrated the
growth-limiting effect of zinc deficiency in otherwise healthy subjects.
Zinc-supplemented children developed increased appetite and thrived
compared to controls. These findings were replicated in studies from
Ontario, and in school-aged children in Texas.34
Breast milk contains zinc citrate,36 which animal studies have found
to be twice as bioavailable as other forms, such as picolinate and sulfate.37
Therefore, infants use the zinc in breast milk more efficiently than that in
formula. During pregnancy, the fetus and other pregnancy tissue account
for around 100 mg of zinc, which the expectant mother must provide,4
and the additional zinc requirement occurs primarily in the last trimester,
when fetal growth is most rapid.34 This suggests that mothers should be
Nutrition for ADHD and Autism 373
advised to optimize their intake with zinc citrate supplementation, at least
throughout pregnancy and breastfeeding.
Zinc, Brain Function and ADHD
Approximately 15% of the zinc in the brain is found in synaptic vesicles,
from which it is released to the extraneuronal space during synaptic trans-
mission. In the surroundings of the synapse, zinc acts upon a variety of neu-
ronal receptors and ionic channels, playing a modulatory role that is not yet
fully understood.38 Within the vesicles, zinc is a cofactor for the produc-
tion of dopamine from -dopa, serotonin from 5HTP, and melatonin from
serotonin (Figure 14.3). Hence, zinc is likely to be an important modula-
tor of synaptic transmission.38 Research suggests that zinc may regulate
N-methyl--aspartate receptors,39 and animal studies have shown that zinc
is an important regulator of gamma-aminobutyric acid receptors, affects
the excitability of hippocampal glutamatergic neurons, and may play an
important role in cerebellar function.40 Indeed, recent studies have shown
evidence for a significant reduction of the combined glutamate/glutamine
to creatine ratio in the right anterior cingulate cortex in patients with
ADHD,41 and striatal glutamate, glutamate/glutamine and creatine concen-
trations were higher in ADHD subjects than in controls, providing evidence
of a striatal creatine/glutamatergic dysregulation in ADHD.42
Several studies have associated low zinc status with symptoms of
ADHD.43–50 Children with the inattentive type of ADHD have been
shown to have significantly lower levels of zinc and ferritin than controls,
but not magnesium and copper. Children with the hyperactive type had
significantly lower levels of zinc, ferritin and magnesium than controls, and
no significant difference with regard to copper. Children with the com-
bined type of ADHD had significantly lower levels of zinc and magnesium
than controls, but not ferritin and copper levels.44
It has been observed in vitro that the dopamine transporter con-
tains a high-affinity zinc-binding site on its extracellular face that mod-
ulates its function. Hence, it has been suggested that in ADHD patients
with low zinc status, zinc supplementation may improve the binding sta-
tus of insufficiently occupied zinc binding sites.45 This is supported by
a number of studies suggesting that response to stimulant medication is
reduced in zinc-deficient ADHD patients and improved by zinc supple-
mentation, resulting in lower medication dosages.51–56 A double-blind pla-
cebo-controlled study of zinc supplementation in ADHD has found that
zinc sulfate was statistically superior to placebo in reducing symptoms of
hyperactivity, impulsivity and impaired socialization, but not in reducing
attention deficits. Zinc supplementation appears to be a useful adjunct in
the treatment for some children with ADHD and low levels of zinc and
Zinc and Thyroid Dysfunction
It has been suggested that children with ADHD and developmental learn-
ing disabilities should be checked for optimum thyroid function as a pos-
sible mediating factor for their difficulties.58 Zinc in plasma and RBCs
has been found to be lower in both hypothyroidism and hyperthyroid-
ism. In one study, RBC zinc in hyperthyroidism was inversely related to
plasma thyroxine concentration. The hyperthyroid group excreted signifi-
cantly greater amounts of zinc than controls, indicating a catabolic pro-
cess. This provides evidence for marked alterations in zinc homeostasis in
persons with thyroid problems.59 Thyroid problems have been found in
some children with ADHD: one study found that thyroxine concentra-
tions were associated with mood symptoms and unusual behaviors, but
were less strongly related to attentional functioning and not related to
Zinc, Histidine and Histamine
The enzyme histidine decarboxylase produces histamine from the amino
acid histidine. Histamine is best known for its release from mast cells as
a response to allergic reactions or tissue damage. However, more impor-
tantly for the treatment of ADHD, histamine is found in high concentra-
tions in neurons in the hypothalamus, from where it mediates arousal and
attention. Pfeiffer and colleagues61 found that approximately 50% of their
outpatient schizophrenics were “histapenic” (low in blood histamine) and
high in blood serum copper, and 20% were histadelic (high in blood his-
tamine) and normal in serum copper. They also found that either group
may be low in serum zinc and/or manganese. Zinc is needed by mast cell
and hippocampus terminal vesicles to store histamine. Without adequate
zinc, histaminergic neurotransmission may be impaired. These two sug-
gested categories, histapenia and histadelia, accounted for around 70% of
the schizophrenias in Pfeiffer’s patients.61
Zinc, Vitamin B6 and Pyroluria
The remaining group of Pfeiffer’s patients had normal blood hista-
mine and serum copper levels. This group had excessive urine excretion
Nutrition for ADHD and Autism 375
of “kryptopyrroles,” also referred to as the “mauve factor.” The pyrroles
combine with pyridoxal (vitamin B6) and then complexes with zinc, pro-
ducing symptoms of vitamin B6 and zinc deficiency. They found that
these patients responded to large supplementary doses of vitamin B6,
zinc and manganese.61 Such individuals have very low RBC zinc and
require heavy supplementation of zinc and vitamin B6. Pyrolurics can
exhibit severe behavioral disorders, have a low frustration threshold and
lose their temper easily. The disorder is familial and is responsible for the
high incidence of behavioral disorders and schizophrenia in families, with
an incidence of 30–40% in schizophrenics and only 5–10% in the normal
population.61 Kryptopyrroles increase in the blood during stress, and zinc
and B6 rapidly become unavailable for neurotransmitter synthesis.
We have found that a number of children diagnosed with ADHD have
very low RBC zinc, the levels of which are resistant to moderate sup-
plementation. These children can be extremely unreasonable, have erratic
moods, can easily lose control when stressed, and often have disruptive
behavioral disorders. We typically test for RBC zinc and copper as well
as serum histamine. In addition, we test for mauve factor in urine, which,
when elevated, is indicative of pyroluria. When we aggressively add zinc
citrate, vitamin B6 (P5P) and manganese to their supplementation regi-
men, their urinary kryptopyrrole excretion reduces significantly and in
most cases behavioral symptoms improve significantly. However, symptoms
return rapidly when supplementation is stopped.
Magnesium is found in the soil and is present in vegetables. In the
hunter–gatherer diet, magnesium-containing foods were common, but
in the last 100 years or so industrialization of food sources, processing of
cereal grains and changing diets have diminished dietary intakes of mag-
nesium and other micronutrients.2,62,63 The magnesium content of vegeta-
bles has declined by 25–80% compared to prior to 1950, and food refining
processes remove most of the available magnesium from grains and cere-
als.63 Consequently, the average American diet affords just over half of the
conservative recommended daily allowance for magnesium.64,65 National
Health and Nutrition Examination Survey data show that a large percent-
age of North Americans fail to meet the recommendations for optimal
calcium, magnesium and vitamin D intake.66
Intestinal interactions between vitamin D, magnesium and calcium
have been demonstrated in both humans and animals.67 The low levels of
vitamin D commonly seen in western society may be a cause for concern,
given that animal studies have shown that severe vitamin D deficiency
during lactation produces marked osteomalacia and secondary hyperpara-
thyroidism in both mothers and their offspring. Vitamin D treatment dur-
ing lactation reversed the mineral, hormonal and skeletal abnormalities in
mothers, but not in offspring.68 Although a substantial amount of magne-
sium absorption occurs independent of vitamin D status, there is evidence
that pharmacological doses of vitamin D increase magnesium absorption
in both vitamin D-deficient and vitamin D-replete animals.67
The diet of Palaeolithic hunter–gatherers and pre-agricultural societies
contained more vegetables, fruit legumes and pulses than meats, and pro-
duced alkaline potential renal acid load values. In contrast, today’s western
diet contains high amounts of animal proteins, grains and dairy products
and produces highly acidic potential renal acid load values.69–72 Therefore,
to buffer the acid and maintain normal blood pH, the blood’s homeo-
static system uses the base minerals such as magnesium, calcium, sodium
and potassium. This leaching of these base minerals leads to a condition
known as latent acidosis, associated with low availability of base miner-
als for biochemistry, including brain function.71 Figure 14.3 illustrates the
importance of magnesium and calcium as cofactors in neurotransmitter
synthesis. Hence, deficiencies in base minerals are likely to have an impact
on monoamine neurotransmitter synthesis and are expected to manifest as
attention deficits and mood disorders.
Magnesium works synergistically with calcium to relax the nervous
system, and symptoms of deficiency include irritability, restlessness, fidg-
etiness, muscle cramps and twitches. Kozielec and Starobrat-Hermelin73
measured hair, plasma and RBC magnesium in 116 children (94 boys
and 20 girls) aged 9–12 years with ADHD. Magnesium deficiency was
found in 95% of the cohort, 77.6% in hair, 58.65% in RBC and 33.6%
in serum. Further analysis indicated an inverse correlation between levels
of magnesium and the Freedom from Distractibility Index. Several stud-
ies have identified magnesium deficiency in the RBCs of children with
Magnesium supplementation has been shown to reduce excitability
and improve concentration in children with low serum and RBC magne-
sium levels.74–76 Forty children with ADHD and 36 controls participated
in a magnesium and vitamin B6 supplementation study. At baseline the
children from the ADHD group showed significantly lower RBC magne-
sium values than controls. Magnesium and vitamin B6 were supplemented
Nutrition for ADHD and Autism 377
for at least 8 weeks. Symptoms of ADHD, including hyperactivity, mood,
aggressiveness and lack of attention at school, were scored from 0 to 4
at different times, and RBC magnesium and ionized calcium levels were
monitored. The supplementation regimen significantly increased RBC
magnesium values, and in almost all cases significantly reduced the clini-
cal symptoms of ADHD. Hyperactivity, mood and aggressiveness were
reduced, and attention at school improved. However, when the supple-
mentation was stopped, clinical symptoms reappeared within a few weeks
along with a decrease in RBC magnesium.78,79 This study suggests that
children with ADHD frequently have low magnesium levels, which is
associated with their symptoms, and that supplementation improves those
EVIDENCE-BASED PRESCRIBING OF NUTRIENTS
In order to maximize brain function, the nutrient cofactors nec-
essary for neurotransmitter synthesis, including those of the enzymes
involved in the conversion stages, must also be optimized. This is partic-
ularly important if the genes that encode these enzymes have polymor-
phisms that reduce their effectiveness, requiring more of the cofactors to
upregulate the enzyme activity. Given what we know about how poor our
western diet is at providing these nutrients, it makes sense for informed
health practitioners to test these in blood and supplement deficiencies. The
following is a list of biomedical tests frequently used at the Behavioural
Neurotherapy Clinic for clients with ADHD: (a) RBC EFAs; (b) RBC
zinc, copper, magnesium, manganese, selenium (in the United States these
are available as a RBC minerals test); (c) serum: vitamin D3, homocyste-
ine, iron studies; (d) extended fecal microbiology analysis from Bioscreen
Medical; (e) SMART DNA genetic screen; and of course a TOVA and
a qEEG analyzed through Neuroguide. Although useful, RBC magne-
sium is a poor indicator of tissue levels and needs. Each laboratory refer-
ence range for blood nutrients is determined from a statistical analysis of
patients’ blood test results in a population low in minerals and is therefore
skewed toward abnormally low ranges. We generally supplement fish oils,
magnesium, zinc, iron, selenium (as Brazil nuts) and vitamin B complex,
and aim for RBC levels that are well into the highest quartile of the range.
We use the SMART DNA test as an indicator of which genes are mutated
and how aggressively we may need to supplement, and we use homocys-
teine levels as a rough guide for the need for methionine and S-adenosyl
methionine, P5P, methylcobalamine, folinic acid and tri-methyl glycine
supplementation. The improvements observed in the TOVA, qEEG and
behavioral measures are often outstanding.
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